Proopiomelanocortin (POMC) is best known to the clinical endocrinologist as the precursor for pituitary ACTH, which is essential for maintaining adrenal cortical function. The most well recognized POMC deficiency syndrome is seen in patients with pituitary disease who fail to secrete ACTH normally and develop secondary adrenal insufficiency. These patients typically complain of anorexia and weight loss, which is corrected by glucocorticoid replacement. Recently, several cases of genetic POMC deficiency have been described, and in contrast to the usual hypopituitary patient with selective pituitary POMC deficiency, these individuals have increased appetite and are obese (1). A similar obesity syndrome has been described in transgenic mice with targeted deletion of the coding region of the Pomc gene (2). These POMC-deficient patients and mice are obese despite having profound secondary adrenal insufficiency. Thus, the effects on energy homeostasis are quite different with generalized POMC deficiency as opposed to the typical hypopituitary patient with POMC deficiency limited to the pituitary. A number of recent studies have established that POMC neurons in the hypothalamus are important regulators of energy homeostasis and that the POMC-derived peptide melanocyte-stimulating hormone (-MSH) and brain melanocortin receptors (MC-Rs) play a key role in this process. This short review focuses on the regulation of feeding behavior and body weight by the brain melanocortin neuropeptide system and the potential implications for the treatment of human obesity.